2018B10 Outline the mechanisms of action of the drugs, with examples, which increase myocardial contractility.

· Intro: contractility, adrenergic signalling

· Drug table: class, example, mechanism of action

Contractility

· Those factors contributing to cardiac performance independent of preload, afterload and heart rate

· ∝ ICF [Ca²⁺]

Adrenergic signalling

· Adrenaline/noradrenaline binds β₁ adrenoceptor, a G_s G protein coupled receptor (GPCR)

· Activation of adenylyl cyclase -> ↑cAMP

· Activation of PKA -> phosphorylation of:

o Myosin: ↑rate at which cross-bridge cycling can occur

o Membrane L-Ca²⁺ and sarcoplasmic reticular ryanodine-sensitive Ca²⁺ channel: ↑Ca²+ influx upon activation

o Troponin I and phospholamban: ↑rate of relaxation

Group	Example	Effect
Naturally occurring catecholamines	Adrenaline Noradrenaline Dopamine	Activate β₁
Synthetic catecholamine	Isoprenaline Dobutamine	Activate β₁
Non-catecholamine β₂ agonist	Salbutamol Terbutaline	Activate cardiac β₂(same cascade as cardiac β₁) More effect on chronotropy and dromotropy than inotropy
Indirect β₁ agonist	Ephedrine Metaraminol	↑NAd release at adrenoceptors
PDE₃ inhibitors	Milrinone Amrinone Aminophylline (non-selective)	↓cAMP breakdown
Ca²⁺ sensitizer	Levosimendan	Ca²⁺ sensitization Stabilises Ca²⁺/troponin C
Other	Calcium	↑gradient for Ca²⁺ into ICF
	Glucagon	Glucagon R: G_s GPCR -> ↑cAMP
	Thyroxine	Permissive effect on catecholamines
	Digoxin	Inhibit cardiac Na⁺K⁺ATPase ↑ICF Na⁺ ↓Activity Na⁺/Ca²⁺ antiporter (3:1) ↑ICF [Ca²⁺]
	Ketamine	↑SNS output from medulla -> ↑adrenaline, noradrenaline release But direct effect neg inotropy (R-ketamine)